6-aryl-imidazo[1,2-a] pyrazin-8-ylamines, method of making, and method of use thereof

ABSTRACT

A novel composition comprises a compound of Formula 1 
                         
the pharmaceutically acceptable salts, hydrates, solvates, crystal forms, diastereomers, prodrugs, or mixtures thereof. The composition is of particular utility in the treatment of kinase-implicated disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of U.S. Provisional PatentApplication Ser. No. 60/409,161 filed Sep. 9, 2002, which is fullyincorporated herein by reference.

BACKGROUND

This invention relates to certain imidazo[1,2-a]pyrazin-8-ylamines andrelated compounds, which when appropriately substituted are modulatorsof kinase activity. This invention also relates to pharmaceuticalcompositions comprising such compounds, and to the use of such compoundsin treating a variety of kinase-associated disorders. Additionally, thisinvention relates to the use of such compounds as probes for theidentification of kinases of therapeutic interest.

One of the central post-translational control elements in eukaryoticsignal transduction is the phosphorylation of the hydroxyl moiety ofserine, threonine, or tyrosine. The phosphorylation state of a givenprotein can govern its enzyme activity, stability, protein-proteinbinding interactions, and cellular distribution. Phosphorylation anddephosphorylation is thus a “chemical switch”, which allows the cell totransmit signals from the plasma membrane to the nucleus and toultimately control gene expression. Although the exact mechanisms ofsignal transduction have yet to be elucidated, kinases are involved inthe control of cell metabolism, growth, differentiation, and apoptosis.These signaling mechanisms affect the onset of cancer, metabolicdisorders (for example diabetes), inflammation, immune system disorders,and neurodegeneration. Certain kinases have been implicated in cellproliferation and carcinogenesis. For example, many human cancers arecaused by disregulation of a normal protein (e.g., when a proto-oncogeneis converted to an oncogene through a gene translocation). Becausekinases are key regulators they are ideal drug design targets.Inhibitors of kinases are among the most important pharmaceuticalcompounds known. Tyrosine kinase inhibitors are useful in inhibitingT-cell proliferation, and thus they are useful as immunosuppressiveagents for the prevention or treatment of graft rejection followingtransplant surgery and for the prevention or treatment of autoimmunediseases such as rheumatoid arthritis and psoriasis. Other tyrosinekinase inhibitors have been described, for example, in U.S. Pat. No.5,593,997 to Dow et al. Erlotinib (CP-358774) is a quinazolinederivative under development as an orally active epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitor for treatment of solid tumorsincluding non-small cell lung cancer (NSCLC), pancreatic cancer, breastcancer, and neck cancer. Gleevec and Imatinib (STI-571), from Novartis,are tyrosine kinase inhibitors indicated for treatment of chronicmyelogenous leukemia (CML), prostate tumors, and gastrointestinalstromal tumors, among others. AstraZeneca is developing gefitinib(ZD-1839; Iressa), an inhibitor of epidermal growth factor receptor 1(EGFR1) tyrosine kinase, for the potential treatment of cancers whichover-express EGF receptors, including non-small cell lung cancer (NSCLC)and other solid tumors such as breast tumors. CEP-1347 (Cephalon Inc.)is an indolcarbazole choline acetyltransferase inhibitor and c-junN-terminal kinase inhibitor for treatment of Alzheimer's disease,Parkinson's disease, and AIDS-related peripheral neuropathy. Cephalon isalso developing CEP-701, an orally active tyrosine kinase inhibitor forthe potential treatment of prostate and other cancers. A PDGF receptortyrosine kinase inhibitor (SU-101, leflunomide) is being investigatedfor treatment of various cancers and rheumatoid arthritis. Sugen hasalso investigated the anti-cancer effects of the FLK-1 tyrosine kinaseinhibitor Semaxanib, particularly for colorectal and lung cancers,leukemia, Kaposi's sarcoma, and others.

Serine/threonine kinase inhibitors are also pharmaceutically important.Eli Lilly is developing LY333531 (ruboxistaurin), an inhibitor ofprotein kinase C beta, for treatment of diabetic macular edema anddiabetic retinopathy. Flavopirodol (Aventis) is a synthetic flavonoidinhibitor of cyclin-dependent kinases, is under development fortreatment of mantle cell lyrnphoma (MCL) and fludar refractory chroniclymphocytic leukemia (CLL). One Raf kinase inhibitor (BAY-43-9006,Bayer) is in development for treatment of solid tumors and myeloidleukemia, and another (ISIS 5132, Isis) is being investigated fortreatment of ovarian cancer. Several p38 mitogen-activated proteinkinase inhibitors (VX-745, VX-702, and VX-850, Vertex, and SCIO-469,Scios) have been investigated for treatment of inflammation, rheumatoidarthritis, and myelodysplastic syndrome (MDS).

Highly selective, cell-permeable modulators of one or more individualkinases would thus be useful in the treatment of variouskinase-implicated disorders. Such compounds would also be useful for thesystematic investigation of the cellular function of one or morekinases, and thus, would provide invaluable tools for the identificationof various kinases of therapeutic interest.

The compounds most closely related structurally to those describedherein are a series of imidazolopyrazines described in WO 02/060492, asJAK inhibitors for the treatment of immune disorders. A series ofpiperazinylimidazo[1,2a]pyrazines are described by Lumma J. Med. Chem.1983, 26, 357–363 as displaying affinity for α-adrenergic receptors.Other imidazo[1,2-a]pyrazines have been reported to be useful asbronchodilators and phosphodiesterase inhibitors (see, for example,Bioorg. Med Chem. 1999, pages 1059–1065), and as GABA_(A) modulators(see for example WO 02/10170). Effects on pulmonary hypertension havealso been reported (see, for example, J. Cardiovasc. Pharmacol. 1998,volume 32, no. 2, pages 213–219). The compounds described in thesepublications are not within the scope of the present invention.

SUMMARY

In one embodiment, this invention is directed to a compositioncomprising a compound of Formula 1:

a pharmaceutically acceptable salt, hydrate, solvate, crystal form,diastereomer, prodrug, or mixtures thereof, wherein

R₁ is hydrogen; cyclo-(C₃–C₆ alkyl)-methyl; straight or branched chainC₁–C₇ alkyl, in which the branched alkyl chains are allowed to also forma 3–7 member heteroalkyl or alkyl ring; sulfonamide; C₁–C₆ alkoxy;(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; mono-or di(C₁–C₆ alkyl)amino, mono- or di (C₁–C₆ alkyl)amino(C₁–C₆ alkyl); orphenyl or heteroaryl ring which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,sulfonamide, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,C₁–C₆ perfluoroalkoxy, —S(C₁–C₆ alkyl), mono- or di(C₁–C₆ alkyl)amino,mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl), or carboxylic acid or ester;

R₂ is straight or branched chain C₁–C₇ alkyl, in which the branchedalkyl chains are allowed to also form a 3–7 member heteroalkyl or alkylring; cyclo-(C₃–C₆ alkyl)-methyl; C₁–C₆ alkoxy;(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; phenylor heteroaryl which may be unsubstituted, mono-, di- or trisubstitutedwith one or more of hydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl, mono-or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S (C₁–C₆ alkyl), orcarboxylic acid or ester; phenyoxy phenyl where each phenyl may beindependently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono-or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), orcarboxylic acid or ester; phenyl or heteroaryl piperazine where thephenyl or heteroaryl ring may be independently unsubstituted, mono-, di-or trisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, mono- ordi(C₁–C₆ alkyl)amino (C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acidor ester; and wherein R₂ can form a 3–7 heteroalkyl or alkyl with R₁₀,R₁₁, or R₁₂;

R₃ is hydrogen; carboxylic acid or ester; straight or branched chainC₁–C₆ alkyl, in which the branched alkyl chains are allowed to also forma 3–7 member heteroalkyl or alkyl ring; phenyl or heteroaryl which maybe unsubstituted, mono-, di- or trisubstituted with one or more ofhydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or ester;phenyoxy phenyl where each phenyl may be independently unsubstituted,mono-, di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), —S (C₁–C₆ alkyl), or carboxylic acid or ester;phenyl or heteroaryl piperazine where the phenyl or heteroaryl ring maybe independently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy- (C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono-or di(C₁–C₆ alkyl)amino, mono- or di (C₁–C₆ alkyl)amino(C₁–C₆ alkyl),—S(C₁–C₆ alkyl), or carboxylic acid or ester;

R₄ is hydrogen; straight or branched chain C₁–C₆ alkyl, in which thebranched alkyl chains are allowed to also form a 3–7 member heteroalkylor alkyl ring; (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl; phenyl or heteroarylwhich may be unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆alkyl)amino, amino (C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid orester; phenyoxy phenyl where each phenyl may be independentlyunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy,C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl, mono-or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S (C₁–C₆ alkyl), orcarboxylic acid or ester; phenyl or heteroaryl piperazine where thephenyl or heteroaryl ring may be independently unsubstituted, mono-, di-or trisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, mono- ordi (C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acidor ester; or form a 3–7 member heteroalkyl or alkyl with Z₁ or R₁;

-   -   X is N or CH    -   Z₁ is

wherein

-   -   each occurrence of R₅ and R₆ is independently hydrogen straight        or branched chain C₁–C₆ alkyl, sulfonamide, or halogen;    -   m is 0, 1, or 2; and    -   R₇ is hydrogen; straight or branched chain C₁–C₆ alkyl; phenyl        which may be unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen, C₁–C₆        alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; and    -   Z₂ is

wherein

-   -   each occurrence of R₈ and R₉ is independently straight or        branched chain C₁–C₆ alkyl, sulfonamide, or halogen;    -   n is 0, 1, or 2; and    -   R₁₀–R₁₃ are each independently hydrogen; straight or branched        chain C₁–C₆ alkyl; phenyl which may be unsubstituted, mono-, di-        or trisubstituted with one or more of hydroxy, nitro, cyano,        amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester;    -   and wherein, when R₃ is hydrogen and R₄ is hydrogen, or when R₃        and R₁ are hydrogen    -   and Z₁ is

wherein m is 0, the combination of Z₂—R₂ is not hydrogen, hydroxy,

-   -   halogen, hydroxyamide, amino, hydroxyalkyl, aminoalkylamide,        alkylamide, arylamide or alkoxy, or    -   wherein when R₃ is hydrogen, R₄ and Z₁ or R₄ and R₁ do not form        a morpholino, piperazinyl, or 1,4-diazepanyl group when the        combination of Z₂—R₂ is hydrogen, hydroxy, halogen,        hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,        arylamide or alkoxy.

In another embodiment, a pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula 1 and apharmaceutically acceptable carrier.

In still another embodiment, a method of treating a kinase-implicateddisorder in a mammal comprises administration to the mammal of apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula 1 and a pharmaceutically acceptable carrier.

In another embodiment, a method for identifying a kinase comprisescontacting an organism, cell, or preparation comprising the kinase witha compound of Formula 1, and detecting modulation of the kinaseactivity.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic illustrating one synthesis of the presentcompounds.

DETAILED DESCRIPTION

The compounds of Formula 1 are novel compounds belonging to the familyof imidazo[1,2-a]pyrazin-8-ylamines and related compounds. Withoutwishing to be bound to any particular theory, it is believed that theinteraction of the compounds of Formula 1 with a kinase (i.e., one ormore kinases) results in modulation of the activity of the kinase(s).The compounds of Formula 1 are thus expected to have therapeuticapplication in mammalian kinase-implicated conditions. As used herein,“modulation” refers to a change in kinase activity as a direct orindirect response to the presence of a compound of Formula 1, relativeto the activity of the kinase in the absence of the compound. The changemay be an increase in activity or a decrease in activity, and may be dueto the direct interaction of the compound with the kinase, or due to theinteraction of the compound with one or more other factors that in turnaffect kinase activity, or both. For example, the presence of thecompound may increase or decrease kinase activity by directly binding tothe kinase, by causing (directly or indirectly) another factor toincrease or decrease the kinase activity, or by (directly or indirectly)increasing or decreasing the amount of kinase present in the cell ororganism.

In one preferred embodiment, novel imidazo[1,2-a]pyrazines may comprisecompounds of general Formula 2:

a pharmaceutically acceptable salt, hydrate, solvate, crystal form,diastereomer, prodrug, or mixtures thereof, wherein

-   -   R₁ is phenyl or heteroaryl ring which may be unsubstituted,        mono-, di- or trisubstituted with one or more of hydroxy, nitro,        cyano, amino, sulfonamide, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy,        C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy, —S(C₁–C₆ alkyl),        mono- or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆        alkyl)amino(C₁–C₆ alkyl), or carboxylic acid or ester;    -   R₂ is phenyl or heteroaryl which may be unsubstituted, mono-,        di- or trisubstituted with one or more of hydroxy, nitro, cyano,        amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; phenyoxy phenyl where each phenyl may be independently        unsubstituted, mono-, di- or trisubstituted with one or more of        hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,        C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl,        mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S (C₁–C₆        alkyl), or carboxylic acid or ester; phenyl or heteroaryl        piperazine where the phenyl or heteroaryl ring may be        independently unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen,        sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        mono- or di (C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or        carboxylic acid or ester; and wherein R₂ can form a 3–7        heteroalkyl or alkyl with R₁₀, R₁₁, or R₁₂;    -   R₃ is hydrogen; or carboxylic acid or ester;    -   R₄ is hydrogen; straight or branched chain C₁–C₆ alkyl, in which        the branched alkyl chains are allowed to also form a 3–7 member        heteroalkyl or alkyl ring; or (C₁–C₆)-alkyl-oxy-(C₁-C₆)alkyl;    -   X is N or CH    -   Z₁ is

wherein

-   -   each occurrence of R₅ and R₆ is independently hydrogen, straight        or branched chain C₁–C₆ alkyl, sulfonamide, or halogen;    -   m is 0, 1, or 2; and    -   Z₂ is

wherein

-   -   R₁₀–R₁₃ are each independently hydrogen; straight or branched        chain C₁–C₆ alkyl; phenyl which may be unsubstituted, mono-, di-        or trisubstituted with one or more of hydroxy, nitro, cyano,        amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester;

-   and wherein, when R₃ is hydrogen and R₄ is hydrogen, or when R₃ and    R₁ are hydrogen    -   and Z₁ is

wherein m is 0, the combination of Z₂—R₂ is not hydrogen, hydroxy,halogen, hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,arylamide or alkoxy, or

-   -   wherein when R₃ is hydrogen, R₄ and Z₁ or R₄ and R₁ do not form        a morpholino, piperazinyl, or 1,4-diazepanyl group when the        combination of Z₂—R₂ is hydrogen, hydroxy, halogen,        hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,        arylamide or alkoxy.

In another preferred embodiment, novel imidazo[1,2-a]pyrazines maycomprise compounds of general Formula 3:

a pharmaceutically acceptable salt, hydrate, solvate, crystal form,diastereomer, prodrug, or mixtures thereof, wherein

-   -   R₁ is hydrogen; cyclo-(C₃–C₆ alkyl)-methyl; straight or branched        chain C₁–C₇ alkyl, in which the branched alkyl chains are        allowed to also form a 3–7 member heteroalkyl or alkyl ring;        sulfonamide; C₁–C₆ alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy;        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; mono- or di(C₁–C₆ alkyl)amino,        mono- or di (C₁–C₆ alkyl)amino(C₁–C₆ alkyl); or phenyl or        heteroaryl ring which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        sulfonamide, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆        perfluoroalkyl, C₁–C₆ perfluoroalkoxy, —S(C₁–C₆ alkyl), mono- or        di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆        alkyl), or carboxylic acid or ester;    -   R₂ is straight or branched chain C₁–C₇ alkyl, in which the        branched alkyl chains are allowed to also form a 3–7 member        heteroalkyl or alkyl ring; cyclo-(C₃–C₆ alkyl)-methyl; C₁–C₆        alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy;        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; phenyl or heteroaryl which may        be unsubstituted, mono-, di- or trisubstituted with one or more        of hydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆        alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl,        mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S (C₁–C₆        alkyl), or carboxylic acid or ester; phenyoxy phenyl where each        phenyl may be independently unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆        perfluoroalkyl, C₁–C₆ perfluoroalkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl,        mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S(C₁–C₆        alkyl), or carboxylic acid or ester; phenyl or heteroaryl        piperazine where the phenyl or heteroaryl ring may be        independently unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen,        sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or        carboxylic acid or ester, and wherein R₂ can form a 3–7        heteroalkyl or alkyl with R₁₂;    -   R₃ is hydrogen; carboxylic acid or ester; straight or branched        chain C₁–C₆ alkyl, in which the branched alkyl chains are        allowed to also form a 3–7 member heteroalkyl or alkyl ring;        phenyl or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; phenyoxy phenyl where each phenyl may be independently        unsubstituted, mono-, di- or trisubstituted with one or more of        hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,        C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl,        mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S (C₁–C₆        alkyl), or carboxylic acid or ester; phenyl or heteroaryl        piperazine where the phenyl or heteroaryl ring may be        independently unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen,        sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        mono- or di (C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or        carboxylic acid or ester;    -   R₄ is hydrogen; straight or branched chain C₁–C₆ alkyl, in which        the branched alkyl chains are allowed to also form a 3–7 member        heteroalkyl or alkyl ring; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl;        phenyl or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino (C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; phenyoxy phenyl where each phenyl may be independently        unsubstituted, mono-, di- or trisubstituted with one or more of        hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,        C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl,        mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S (C₁–C₆        alkyl), or carboxylic acid or ester; phenyl or heteroaryl        piperazine where the phenyl or heteroaryl ring may be        independently unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen,        sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,        C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        mono- or di (C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or        carboxylic acid or ester; or form a 3–7 member heteroalkyl or        alkyl with Z₁ or R₁;    -   X is N or CH    -   Z₁ is

wherein

-   -   each occurrence of R₅ and R₆ is independently hydrogen straight        or branched chain C₁–C₆ alkyl, sulfonamide, or halogen;    -   m is 0, 1, or 2; and    -   R₇ is hydrogen; straight or branched chain C₁–C₆ alkyl; phenyl        which may be unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen, C₁–C₆        alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester; and    -   wherein R₁₂ and R₁₃ are each independently hydrogen; straight or        branched chain C₁–C₆ alkyl; phenyl which may be unsubstituted,        mono-, di- or trisubstituted with one or more of hydroxy, nitro,        cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, mono- or di(C₁–C₆ alkyl)amino,        amino(C₁–C₆ alkyl), —S (C₁–C₆ alkyl), or carboxylic acid or        ester; or heteroaryl which may be unsubstituted, mono-, di- or        trisubstituted with one or more of hydroxy, nitro, cyano, amino,        halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆        perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,        (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,        amino (C₁C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or        ester.

The following definitions are used herein.

As used herein, when any variable occurs more than one time in theformulas, its definition on each occurrence is independent of itsdefinition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference to “a” kinase or “the”kinase is inclusive of one or more kinases.

By “heteroaryl” is meant aromatic systems containing at least oneheteroatom, for example, oxygen, nitrogen, sulfur, and the like, as wellas combinations comprising at least one of the foregoing heteroatoms.Suitable heteroaryl groups include, for example (as numbered from thelinkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl,2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5–pyrimidinyl,2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl,thiazolinyl, thiadiazolinyl, tetrazolyl, and the like.

By “heteroalkyl” is meant an aliphatic ring containing at least 1 carbonatom in addition to 1–3 heteroatoms independently selected from oxygen,sulfur, or nitrogen, and the like, as well as combinations comprising atleast one of the foregoing heteroatoms.

By “sulfonamide” is meant —S(O)₂N— in either S-linked or N-linkedorientation, where the nitrogen atom can be unsubstituted, mono- ordisubstituted with cyclo-(C₃–C₆ alkyl)-methyl; straight or branchedchain C₁–C₆ alkyl, in which the branched alkyl chains are allowed toalso form a 3–7 member alkyl or heteroalkyl ring.

By “piperazine” is meant unsubstituted piperazine, as well aspiperazines independently substituted on 1–4 carbon atoms with hydroxy,cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, mono- or di(C₁–C₆alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl), sulfonamide.

By “C₁–C₆ alkyl” is meant straight or branched chain alkyl groups orcycloalkyl groups having 1–6 carbon atoms, such as, for example, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. Preferred C₁–C₆ alkyl groups are methyl, ethyl, propyl,butyl, cyclopropyl, cyclopropylmethyl, cyclohexyl, cycloheptyl,norbomyl, and the like.

By “C₁–C₆ alkoxy” is meant an alkyl group of indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy. Preferred alkoxy groups herein are C₁–C₄ alkoxy groups.

The term “halogen” includes fluorine, chlorine, bromine, and iodine.

If the compounds of Formula 1 have asymmetric centers, then Formula 1includes all of the optical isomers and mixtures thereof. In addition,compounds with carbon-carbon double bonds may occur in Z- and E-forms,with all isomeric forms of the compounds being included. These compoundscan be, for example, racemates or optically active forms. In thesesituations, the single enantiomers, i.e., optically active forms can beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. Where a compound ofFormula 1 exists in various tautomeric forms, the invention is notlimited to any one of the specific tautomers, and includes alltautomeric forms of the compound.

Representative compounds of the present invention, which are encompassedby Formula 1, include, but are not limited to their pharmaceuticallyacceptable acid addition salts. Non-toxic “pharmaceutically acceptablesalts” include, but are not limited to salts with inorganic acids, suchas hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate,sulfinate, or nitrate salts; or salts with an organic acid, such asmalate, maleate, famarate, tartrate, succinate, citrate, acetate,lactate, methanesulfonate, p-toluenesulfonate, 2–hydroxyethylsulfonate,benzoate, salicylate, stearate, and alkanoate such as acetate,HOOC—(CH₂)_(n)—COOH where n is 0–4, and the like salts. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium, and ammonium.

In addition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, it maybe produced by dissolving the free base in a suitable organic solventand treating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts encompassed by Formula 1.

The present invention also encompasses the prodrugs of the compounds ofFormula 1, for example acylated prodrugs of the compounds of Formula 1.Those skilled in the art will recognize various synthetic methodologiesthat may be used to prepare non-toxic pharmaceutically acceptableacylated and other prodrugs of the compounds encompassed by Formula 1.

Methods for obtaining the compounds described herein are known to thoseof ordinary skill in the art, suitable procedures being described, forexample, in the references cited herein.

As mentioned above, it is believed that the interaction of the compoundsof Formula 1 with one or more kinases results in modulation of theactivity of the one or more kinases. Suitable kinases include but arenot limited to tyrosine kinases and serine/threonine kinases, which maybe classified as including the AGC group (cyclic nucleotide regulatedfamily) of protein kinases, which includes the cyclic nucleotideregulated protein kinase family (e.g., PKA and PKG), thediacylglycerol-activated/phospholipid-dependent family protein kinase Cfamily (e.g., PKC), the PKA and PKC-related family (e.g., RAC and Akt),the kinases that phosphorylate G protein-coupled receptors family, thebudding yeast AGC-related protein kinase family, the kinases thatphosphorylate ribosomal protein S6 family, the budding yeast DBF2/20family, the flowering plant PVPKl protein kinase homolog family, andother AGC related kinase families.

The CaMK (calcium calmodulin dependent) group of protein kinasesincludes kinases regulated by Ca²⁺/CaM and close relatives family, theKIN1/SNF1/Nim1 family, and other related CaMK related kinase families.The CMGC group (named because it includes the cyclin-dependent kinases)includes the cyclin-dependent kinases (e.g., CDKs) and close relativesfamily, the ERK (e.g., MAP) kinase family, the glycogen synthase 3(e.g., GSK3) family, the casein kinase II family, the Clk family andother CMGC kinases.

The PTK group of protein kinases includes protein-tyrosine kinases thatmay be nonmembrane-spanning or membrane-spanning tyrosine kinases. ThePTK group of protein kinases includes the Src family, the Tek/Atkfamily, the Csk family, the Fes (Fps) family, the Abl family, theSyk/ZAP70 family, the Ttk2/Jakl family, the Ack family, the focaladhesion kinase (Fak) family, the epidermal growth factor receptorfamily, the Eph/Elk/Eck receptor family, the Axl family, the Tie/Tekfamily, the platelet-derived growth factor receptor family, thefibroblast growth factor receptor family, the insulin receptor family,the LTK/ALK family, the Ros/Sevenless family, the Trk/Ror family, theDDR/TKT family, the hepatocyte growth factor receptor family, thenematode Kin15/16 family and other PTK kinase families.

The OPK group (other protein kinases) includes the Polo family, theMEK/STE7 family, the PAK/STE20 family, the MEKK/STE11 family, the NimAfamily, the wee1/mik1 family, the kinases involved in transcriptionalcontrol family, the Raf family, the Activin/TGFb receptor family, theflowering plant putative receptor kinases and close relatives family,the PSK/PTK leucine zipper domain family, the casein kinase I family,the PKN prokaryotic protein kinase family and other OPK protein kinasefamilies. A large number of kinases are found in G. Hardie et al.,Protein Kinase Facts Book 0–12–324719–5 (1995).

The compounds of the present invention belong to the family ofimidazo[1,2-a]pyrazines. Other imidazo[1,2-a]pyrazines have beenreported to be useful as bronchodilators and phosphodiesteraseinhibitors (see, for example, Bioorg. Med Chem. 1999, pages 1059–1065).Effects on pulmonary hypertension have also been reported (see, forexample, J. Cardiovasc. Pharmacol. 1998, volume 32, no. 2, pages213–219).

The present inventors have discovered new imidazo[1,2-a]pyrazines anddetermined that they are active as kinase inhibitors. The inhibitors ofthe present invention are expected to have therapeutic application inmammalian kinase-implicated conditions.

Accordingly, a method of treating a kinase-implicated disease orcondition in a mammal, preferably a human, comprises administration tothe mammal of a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula 1 and a pharmaceuticallyacceptable carrier. As used herein “therapeutically effective” includesalleviation of disease, disease symptoms, preventative, and prophylactictreatment.

Kinases are implicated in a large variety of diseases, as certainmutations in protein kinases can lead to activation of pathways causing,for example, the production of tumors, while other mutations in proteinkinases block pathways and prevent a response. Some diseases that arelinked to mutations in protein kinases are listed in the KinMutBasedatabase (http://www.uta.fi/imt/bioinfo/KinMutBase/) (Stenberg et al.,Nucleic Acids Research, Vol. 28, pp. 369–372, 2000). Diseases caused byprotein kinase mutations include X-linked agammaglobulinemia (XLA), andnon-insulin dependent diabetes mellitus (NIDDM), and severe combinedimmunodeficiency (SCID). Mutations related to tumor development havebeen liked to such diseases as Hirschprung's disease, multiple endocrineneoplasia type 2 (MEN2) a and b, medullary thyroid carcinoma (FMTC),papillary renal carcinoma (HPRC), and Peutz-Jeghers syndrome.

Mutations in growth factor receptor kinases are linked to diseases suchas mastocytosis, systemic mast cell disease, piebaldism,hypochondroplasia, thanatophoric dysplasia, and skeletal dysplasia.Other protein kinase-linked diseases include Coffin-Lowry syndrome,congenital insensitivity to pain with anhidrosis (CIPA), hypertension,vascular dysplasia, errors in vascular morphogenesis, and X-linkedmental retardation. Mutations in protein kinases have also been linkedto neurodegenerative diseases such as amyotrophic lateral sclerosis(ALS) and Alzheimer's disease (AD).

Other diseases associated with protein kinases include Gaucher disease,hypochromic anemia, granulomatous disease, ataxia-telangiectasia,familial hypercholesterolemia, certain types of muscular dystrophy suchas Driefuss-Emory type, cystic fibrosis, type 1 hyperlipoproteinemia,Treacher Collins Franceschetti syndrome 1, Tay-Sachs disease, type 1neurofibromatosis, adenomatous polyposis of the colon, X-linkedichthyosis, and Beckwith-Weidemann Syndrome.

Altered PKA (cyclic AMP-dependent protein kinase) expression isimplicated in a variety of disorders and diseases including cancer,thyroid disorders, diabetes, atherosclerosis, and cardiovasculardisease. Altered MAP (mitogen-activated protein) kinase expression isimplicated in a variety of disease conditions including cancer,inflammation, immune disorders, and disorders affecting growth anddevelopment. RTKs (receptor tyrosine kinases), CDKs and STKs(serine/threonine kinases) have all been implicated in a host ofpathogenic conditions including, significantly, large number of diversecancers. Others pathogenic conditions which have been associated withPTKs include, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis,angiogenesis, restinosis, ocular diseases, rheumatoid arthritis andother inflammatory disorders, autoimmune disease, and a variety of renaldisorders.

Preferably, the conditions, diseases and/or disorders that can beaffected using compounds and compositions according to the inventioninclude, but are not limited to, psoriasis, cancer (for example, chronicmyelogenous leukemia, gastrointestinal stromal tumors, non-small celllung cancer, breast cancer, ovarian cancer, recurrent ovarian cancer,prostate cancer such as hormonal refractory prostate cancer, kidneycancer, head and neck cancer, or colorectal cancer), immunoregulation(graft rejection), atherosclerosis, rheumatoid arthritis, Parkinson'sdisease, Alzheimer's disease, diabetes (for example insulin resistanceor diabetic retinopathy), septic shock, and the like.

In a preferred embodiment, the condition is cancer. A method of treatingcancer comprising administering to a mammal in need thereof atherapeutically effective amount of a compound of Formula 1, and atherapeutically effective amount of an antitumor therapeutic. Treatmentwith the antitumor therapeutic may be prior to treatment with theinventive compounds, during treatment, following treatment with thecompounds, or a combination thereof. Suitable antitumor therapeutics areknown, and are preferably a chemotherapeutic agent, for examplemitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide,doxorubicin, or a combination comprising at least one of the foregoingchemotherapeutic agents. Radiotherapeutic antitumor agents may also beused, alone or in combination with chemotherapeutic agents.

In another embodiment, pharmaceutical compositions comprising at leastone compound of Formula 1, together with one or more non-toxic,pharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. Such pharmaceuticalcompositions include packaged pharmaceutical compositions for treatingdisorders responsive to modulation of kinase activity. A packagedpharmaceutical composition includes a container holding atherapeutically effective amount of at least compound of Formula 1 andinstructions (e.g., labeling) indicating that the contained compositionis to be used for treating a disorder responsive to kinase modulation inthe patient. Those of ordinary skill in the art will also recognize awide variety of non-toxic pharmaceutically acceptable solvents that maybe used to prepare solvates of the compounds of the invention, such aswater, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide(DMSO).

The compounds of general Formula 1 may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles. Oral administration in theform of a pill, capsule, elixir, syrup, lozenge, troche, or the like isparticularly preferred. The term parenteral as used herein includessubcutaneous injections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. The pharmaceutical compositions containingcompounds of general Formula 1 may be in a form suitable for oral use,for example, as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent, and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring, and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin, or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation may also be sterile injectable solutionor suspension in a non-toxic parentally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compounds of general Formula 1 may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula 1 may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives, andbuffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions so that theanimal takes in an appropriate quantity of the composition along withits diet. It will also be convenient to present the composition as apremix for addition to the feed or drinking water.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per human patientper day). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. For the treatmentof eating disorders, including obesity, a dosage regimen of 1 or 2 timesdaily is particularly preferred. For the treatment of impotence a singledose that rapidly reaches effective concentrations is desirable.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding, and desirablein vitro and in vivo half-lives. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat peripheral disorders are oftenpreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B 1996, volume 677, pages 1–27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition 1998, volume 26, pages 1120–1127).

In another embodiment, the compounds of Formula 1 are also useful asprobes for the localization of kinases of therapeutic interest, that is,for both in vivo and in vitro identification and isolation the specificproteins to which it binds. A method for identifying a kinase comprisescontacting an organism, cell, or preparation comprising the kinase withcompound or salt according to Formula 1 and detecting modulation of anactivity of the kinase. Suitable methods for detecting kinase modulationare known, for example those described herein.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1

This example provides an exemplary synthesis of compounds of Formula 1(FIG. 1).

6,8-dibromoimidazo[1,2-a]pyrazine (3). A solution of 1.00 eq. of3,5-dibromo-2-aminopyrazine 1 in ethanol is treated with 2.00 eq. ofα-bromo-aldehyde 2 at RT and heated for 48 hr. The solvent is removedunder reduced pressure and the residue is triturated with diethyl etherand filtered to give the HBr salt 3.

8-Amino-6-bromoimidazo[1,2-a]pyrazine (4). Procedure 1: A mixture of1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 in 28% Ammonia/water solutionor 40% aqueous methyl amine is heated to between 80 to 90° C. for 24 hr.The resulting mixture is partitioned between CH₂Cl₂ and H₂O. The aqueouslayer is extracted with CH₂Cl₂ and the combined organic extracts aredried over Na₂SO₄. The solvent is removed under reduced pressure and theresulting residue is crystallized from ethanol to yield 4.

Procedure 2: A solution of 1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 inN,N-dimethylacetamide is treated with 2.00 eq. of benzylamine and 3.00eq. of K₂CO₃. The resulting mixture is heated to 100° C. for 24 to 48hours, cooled to RT and partitioned between H₂O/CH₂Cl₂. The aqueouslayer is extracted with CH₂Cl₂ and combined organic extracts are driedover Na₂SO₄. The solvent is removed under reduced pressure and theresulting residue is purified by flash chromatography (3:7EtOAc/Hexanes) to yield 4.

8-Amino-6-aryl-imidazo[1,2-a]pyrazine (5). Procedure: A mixture of 1.00eq. of 8-amino-6-bromoimidazo[1,2-a]pyrazine, 3.00 eq. of R₄-sustitutedboronic acid, and 0.10 eq. of Pd²⁺(PPh₃)₄, in 6.00 eq. of 1N Na₂CO₃/dmeis heated to 90° C. for 24 hr. The mixture is cooled to RT andpartitioned between 10% AcOH/CH₂Cl₂. The aqueous phase is extracted withCH₂Cl₂ and combined extracts are dried over Na₂SO₄. The solvent isremoved under reduced pressure and the resulting residue is purified byflash chromatography (1–5% 2M NH₃/MeOH/CH₂Cl₂) to yield 5.

1-[4-(8-Amino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-phenyl-urea (8).(FIG. 1) Procedure: A mixture of 1.00 eq. of6-(4-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamine, 1.50 eq. ofphenylisocyanate, and 2.00 eq. of N-methylmorpholine, in toluene ismixed at room temperature for 2 hr. The mixture is partitioned between 1N NaOH and ethyl acetate and extracted three times. The organic extractsare combined and dried over MgSO₄. The solvent is removed under reducedpressure and the resulting residue is purified by flash chromatography(50% ethyl acetate/hexanes) to yield 8.

EXAMPLE 2

The following compounds were prepared in accordance with FIG. 1 usingthe above procedures.

-   -   (a)        1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(2-(chloro-phenyl)-urea,        MF═C₂₇H₂₂Cl₂N₆O, MW═517.41 Mass Spec m/z (M⁺+1) 517.13;    -   (b)        1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-(chloro-phenyl)-urea,        MF═C₂₇H₂₂Cl₂N₆O, MW═517.41 Mass Spec m/z (M⁺+1) 517.12;    -   (c)        1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(2-(methoxy-phenyl)-urea,        MF═C₂₈H₂₅ClN₆O₂, MW═512.99 Mass Spec m/z (M⁺+1) 513.28;    -   (d) 1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo        [1,2-a]pyrazin-6-yl}-phenyl)-3-(4-(chloro-phenyl)-urea,        MF═C₂₇H₂₂Cl₂N₆O, MW═517.41 Mass Spec m/z (M⁺+1) 517.23;    -   (e)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-(chloro-phenyl)-urea,        MF═C₂₇H₂₂Cl₂N₆O, MW═517.41 Mass Spec m/z (M⁺+1) 516.99;    -   (f)        1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-(trifluoromethyl-phenyl)-urea,        MF═C₂₈H₂₂ClF₃N₆O, MW═550.96 Mass Spec m/z (M⁺+1) 551.04;    -   (g)        1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-(trifluoromethoxy-phenyl)-urea,        MF═C₂₈H₂₂ClF₃N₆O₂, MW═566.96 Mass Spec m/z (M⁺+1) 567.02;    -   (h)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(2(methylsulfanyl-phenyl)-urea,        MF═C₂₈H₂₅CIN₆OS, MW═529.05 Mass Spec m/z (M⁺+1) 529.26;    -   (i)        1-(3-{8-[Methyl-(4-methyl-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(2-(methylsulfanyl-phenyl)-urea,        MF═C₂₉H₂₈N₆OS, MW═508.64 Mass Spec m/z (M⁺+1) 509.17;    -   (j)        1-(4Chloro-phenyl)-3-(3-{8-[methyl-(4-methyl-benzyl)-amino]-imidazo[-        1,2-a]pyrazin-6-yl}-phenyl)-urea, MF═C₂₈H₂₅ClN₆O, MW═496.99 Mass        Spec m/z (M⁺+1) 497.17;    -   (k)        1-(3-{8-[Methyl-(4-methyl-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-o-tolyl-urea,        MF═C₂₉H₂₈N₆O, MW═476.57 Mass Spec m/z (M⁺+1) 477.26;    -   (l)        1-(4-Chloro-phenyl)-3-{3-[8-(3,4-dihydro-1H-isoquinolin-2-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₈H₂₃ClN₆O, MW═494.97 Mass Spec m/z (M⁺+1) 494.99;    -   (m)        1-{3-[8-(3,4-Dihydro-1H-isoquinolin-2-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methylsulfanyl-phenyl)-urea,        MF═C₂₉H₂₆N₆OS, MW═506.62 Mass Spec m/z (M⁺+1) 506.98;    -   (n)        1-{3-[8-(3,4-Dihydro-1H-isoquinolin-2-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-o-tolyl-urea,        MF═C₂₉H₂₆N₆O, MW═474.55 Mass Spec m/z (M⁺+1) 475.04;    -   (o)        1-{3-[8-(3,4-Dihydro-1H-isoquinolin-2-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-phenyl)-urea,        MF═C₂₉H₂₆N₆O₂, MW═490.55 Mass Spec m/z (M⁺+1) 491.27;    -   (p)        8-[(4-Chloro-benzyl)-methyl-amino]-6-{3-[3-(2-trifluoromethyl-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazine-3-carboxylic        acid ethyl ester, MF═C₃₁H₂₆ClF₃N₆O₃, MW═623.02 Mass Spec m/z        (M⁺+1) 623.01;    -   (q)        8-[(4-Chloro-benzyl)-methyl-amino]-6-[3-(3-o-tolyl-ureido)-phenyl]-imidazo[1,2-a]pyrazine-3-carboxylic        acid ethyl ester, MF═C₃₁H₂₉ClN₆O₃, MW═569.05 Mass Spec m/z        (M⁺+1) 569.05;    -   (r)        8-[(4-Chloro-benzyl)-methyl-amino]-6-{3-[3-(4-chloro-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazine-3-carboxylic        acid ethyl ester, MF═C₃₀H₂₆Cl₂N₆O₃, MW═589.47 Mass Spec m/z        (M⁺+1) 589.01;    -   (s)        1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[methyl-(4-methyl-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₈H₂₄ClFN₆O, MW═514.98 Mass Spec m/z (M⁺+1) 515.00;    -   (t)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-chloro-4-fluoro-phenyl)-urea,        MF═C₂₇H₂₁Cl₂FN₆O, MW═535.39 Mass Spec m/z (M⁺+1) 534.99;    -   (u)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-benzyl)-3-(4-chloro-phenyl)-urea,        MF═C₂₈H₂₄Cl₂N₆O, MW═531.43 Mass Spec m/z (M⁺+1) 531.08;    -   (v)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-benzyl)-3-(3-chloro-4-fluoro-phenyl)-urea,        MF═C₂₈H₂₃Cl₂FN₆O, MW═549.42 Mass Spec m/z (M⁺+1) 549.06;    -   (w)        1-(3-{8-[(4-Chloro-benzyl)-ethyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-o-tolyl-urea,        MF═C₂₉H₂₇ClN₆O, MW═511.01 Mass Spec m/z (M⁺+1) 511.28;    -   (x)        1-(3-{8-[(4-Chloro-benzyl)-ethyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-phenyl)-urea,        MF═C₂₈H₂₄Cl₂N₆O, MW═531.43 Mass Spec m/z (M⁺+1) 530.89;    -   (y)        1-(3-{8-[(4-Chloro-benzyl)-ethyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-chloro-4-fluoro-phenyl)-urea,        MF═C₂₈H₂₃Cl₂FN₆O, MW═549.42 Mass Spec m/z (M⁺+1) 548.90;    -   (z)        1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-o-tolyl-urea,        MF═C₃₀H₂₉ClN₆O, MW═525.04 Mass Spec m/z (M⁺+1) 525.32;    -   (aa)        1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-chloro-4-fluoro-phenyl)-urea,        MF═C₂₉H₂₅Cl₂FN₆O, MW═563.45 Mass Spec m/z (M⁺+1) 567.23;    -   (bb)        1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-o-tolyl-urea,        MF═C₃₁H₃₁ClN₆O, MW═539.07 Mass Spec m/z (M⁺+1) 539.31;    -   (cc)        1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-phenyl)-urea,        MF═C₂₉H₂₆Cl₂N₆O, MW═545.46 Mass Spec m/z (M⁺+1) 545.02;    -   (dd)        1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₃₀H₂₆ClF₃N₆O, MW═579.01 Mass Spec m/z (M⁺+1) 579.01;    -   (ee)        1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-phenyl)-urea,        MF═C₃₀H₂₈Cl₂N₆O, MW═559.48 Mass Spec m/z (M⁺+1) 559.02;    -   (ff)        1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₃₁H₂₈ClF₃N₆O, MW═593.04 Mass Spec m/z (M⁺+1) 593.03;    -   (gg)        1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-chloro-4-fluoro-phenyl)-urea,        MF═C₃₀H₂₇Cl₂FN₆O, MW═577.48 Mass Spec m/z (M⁺+1) 577.00;    -   (hh)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₈H₂₂ClF₃N₆O, MW═550.96 Mass Spec m/z (M⁺+1) 551.02;    -   (a) (ii)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-o-tolyl-urea,        MF═C₂₈H₂₅ClFN₆O, MW═496.99 Mass Spec m/z (M⁺+1) 496.99;    -   (jj)        1-{3-[8-(Benzyl-methyl-amino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea,        MF═C₂₇H₂₃ClN₆O, MW═482.96 Mass Spec m/z (M⁺+1) 483.23;    -   (kk)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-trifluoromethoxy-phenyl)-urea,        MF═C₂₈H₂₂ClF₃N₆O₂, MW═566.96 Mass Spec m/z (M⁺+1) 567.10;    -   (ll)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(5-fluoro-2-trifluoromethyl-phenyl)-urea,        MF═C₂₈H₂₁ClF₄N₆O, MW═568.96 Mass Spec m/z (M⁺+1) 569.12;    -   (mm)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3,5-dichloro-phenyl)-urea,        MF═C₂₇H₂₁Cl₃N₆O, MW═551.85 Mass Spec m/z (M⁺+1) 551.04;    -   (nn)        1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3,4-dichloro-phenyl)-urea,        MF═C₂₇H₂₁Cl₃N₆O, MW═551.85 Mass Spec m/z (M⁺+1) 551.02;    -   (oo)        1-(3-{8-[(2-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-phenyl)-urea,        MF═C₂₇H₂₂Cl₂N₆O, MW═517.40 Mass Spec m/z (M⁺+1) 517.13;    -   (pp)        1-{3-[8-(Methyl-pyridin-4-ylmethyl-amino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₇H₂₂F₃N₇O, MW═517.50 Mass Spec m/z (M⁺+1) 518.34;    -   (qq)        1-(4-Chloro-benzyl)-3-(3-{8-[(4-chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₈H₂₄Cl₂N₆O, MW═531.43 Mass Spec m/z (M⁺+1) 531.3;    -   (rr)        1-(3-{8-[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-phenyl)-urea,        MF═C₂₉H₂₆Cl₂N₆O₂, MW═561.46 Mass Spec m/z (M⁺+1) 561.28;    -   (ss)        1-(3-{8-[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₃₀H₂₆ClF₃N₆O₂, MW═595.01 Mass Spec m/z (M⁺+1) 595.3;    -   (tt)        1-(3-{8-[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-3-fluoro-phenyl)-urea,        MF═C₂₉H₂₅Cl₂FN₆O₂, MW═579.45 Mass Spec m/z (M⁺+1) 579.28;    -   (uu)        1-(3-{8-[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-urea,        MF═C₃₅H₃₉ClN₈O₂, MW═639.19 Mass Spec m/z (M⁺+1) 639.46;    -   (vv)        (2-Methoxy-benzyl)-{6-[3-(4-methoxy-benzylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl}-amine,        MF═C₂₈H₂₇N₅O₂, MW═465.55 Mass Spec m/z (M⁺+1) 466.09;    -   (ww)        1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-phenyl-urea,        MF═C₂₇H₂₄N₆O₂, MW═464.52 Mass Spec m/z (M⁺+1) 465.05;    -   (xx)        1-(2-Chloro-phenyl)-3-{4-[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₇H₂₃ClN₆O₂, MW═498.96 Mass Spec m/z (M⁺+1) 499.18;    -   (yy)        1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-phenyl)-urea,        MF═C₂₈H₂₆N₆O₃, MW═494.55 Mass Spec m/z (M⁺+1) 495.23;    -   (zz)        1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-methoxy-phenyl)-urea,        MF═C₂₈H₂₆N₆O₃, MW═494.55 Mass Spec m/z (M⁺+1) 495.21;    -   (aaa)        N-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzenesulfonamide,        MF═C₂₆H₂₂ClN₅O₂S, MW═504.00 Mass Spec m/z (M⁺+1) 503.80;    -   (bbb)        N-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide,        MF═C₂₇H₂₂ClN₅O, MW═467.95 Mass Spec m/z (M⁺+1) 467.84;    -   (ccc)        4-Chloro-N-(3-{8-[(4-chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide,        MF═C₂₇H₂₁Cl₂N₅O, MW═502.39 Mass Spec m/z (M⁺+1) 502.00;    -   (ddd)        2-Chloro-N-(3-{8-[(4-chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide,        MF═C₂₇H₂₁Cl₂N₅O, MW═502.39 Mass Spec m/z (M⁺+1) 502.02;    -   (eee)        (4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-piperidin-1-yl-methanone,        MF═C₂₆H₂₆ClN₅O, MW═459.97 Mass Spec m/z (M⁺+1) 460.25;    -   (fff)        (4-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-piperidin-1-yl-methanone,        MF═C₂₆H₂₆ClN₅O, MW═459.97 Mass Spec m/z (M⁺+1) 460.26;    -   (ggg)        4-{6-[4-(Piperidine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic        acid ethyl ester, MF═C₂₇H₂₇N₅O₃, MW═469.94 Mass Spec m/z (M⁺+1)        470.08;    -   (hhh)        4-(6-{3-[3-(4-Chloro-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic        acid ethyl ester, MF═C₂₈H₂₃ClN₆O₃, MW═526.97 Mass Spec m/z        (M⁺+1) 527.05;    -   (iii)        4-(6-{3-[3-(2-Methylsulfanyl-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic        acid ethyl ester, MF═C₂₉H₂₆N₆O₃S, MW═538.62 Mass Spec m/z (M⁺+1)        539.19;    -   (jjj)        {4-[8-(4-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-piperidin-1-yl-methanone,        MF═C₂₄H₂₂ClN₅O, MW═431.92 Mass Spec m/z (M⁺+1) 432.03;    -   (kkk)        3-Methoxy-N-{3-[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide,        MF═C₂₈H₂₅N₅O₃, MW═479.53 Mass Spec m/z (M⁺+1) 479.99;    -   (lll)        2-Methoxy-N-{3-[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide,        MF═C₂₈H₂₅N₅O₃, MW═479.53 Mass Spec m/z (M⁺+1) 480.27;    -   (mmm)        1-(3-Chloro-4-fluoro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF═C₂₅H₁₈ClFN₆O, MW═472.90 Mass Spec m/z (M⁺+1) 473.01;    -   (nnn)        1-(4-Chloro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF═C₂₅H₁₉ClN₆O, MW═454.91 Mass Spec m/z (M⁺+1) 455.04;    -   (ooo)        1-[3-(8-Phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₆H₁₉F₃N₆O, MW═488.46 Mass Spec m/z (M⁺+1) 489.01;    -   (ppp)        1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF═C₂₆H₁₈ClF₃N₆O, MW═522.91 Mass Spec m/z (M⁺+1) 523.11;    -   (qqq)        1-(4-Chloro-phenyl)-3-{3-[8-(4-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₅H₁₈Cl₂N₆O, MW═489.36 Mass Spec m/z (M⁺+1) 489.20;    -   (rrr)        1-{3-[8-(4-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₆H₁₈ClF₃N₆O, MW═522.91 Mass Spec m/z (M⁺+1) 523.13;    -   (sss)        1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(3-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₅H₁₇Cl₂FN₆O, MW═507.35 Mass Spec m/z (M⁺+1) 507.13;    -   (ttt)        1-(4-Chloro-phenyl)-3-{3-[8-(3-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₅H₁₈Cl₂N₆O, MW═489.36 Mass Spec m/z (M⁺+1) 489.13;    -   (uuu)        1-{3-[8-(3-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₆H₁₈ClF₃N₆O, MW═522.91 Mass Spec m/z (M⁺+1) 523.12;    -   (vvv)        1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₅H₁₇Cl₂FN₆O, MW═507.35 Mass Spec m/z (M⁺+1) 507.09;    -   (www)        1-[3-(8-Phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,        MF═C₂₆H₁₈F₃N₅O, MW═473.45 Mass Spec m/z (M⁺+1) 474.08;    -   (xxx)        1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[(pyridin-2-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₅H₁₉ClFN₇O, MW═487.92 Mass Spec m/z (M⁺+1) 488.09;    -   (yyy)        1-(4-Chloro-phenyl)-3-(3-{8-[(pyridin-3-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₅H₂₀ClN₇O, MW═469.93 Mass Spec m/z (M⁺+1) 470.21;    -   (zzz)        1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[(pyridin-3-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₅H₁₉ClFN₇O, MW═487.92 Mass Spec m/z (M⁺+1) 488.12;    -   (aaaa)        1-(4-Chloro-phenyl)-3-(3-{8-[(pyridin-4-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₅H₂₀ClN₇O, MW═469.93 Mass Spec m/z (M⁺+1) 470.21;    -   (bbbb)        1-(3-{8-[(Pyridin-4-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₆H₂₀F₃N₇O, MW═503.48 Mass Spec m/z (M⁺+1) 504.17;    -   (cccc)        1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[(pyridin-4-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea,        MF═C₂₅H₁₉ClFN₇O, MW═487.92 Mass Spec m/z (M⁺+1) 488.20;    -   (dddd)        1-{3-[8-(Pyridin-4-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₅H₁₈F₃N₇O, MW═489.45 Mass Spec m/z (M⁺+1) 490.16;    -   (eeee)        1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(pyridin-4-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₄H₁₇ClFN₇O, MW═473.89 Mass Spec m/z (M⁺+1) 474.12;    -   (ffff)        1-(4-Chloro-phenyl)-3-(3-{8-[(pyridin-2-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea        MF═C₂₅H₂₀ClN₇O, MW═469.93 Mass Spec m/z (M⁺+1) 470.12;    -   (gggg)        1-(3-{8-[(Pyridin-2-ylmethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₆H₂₀F₃N₇O, MW═503.48 Mass Spec m/z (M⁺+1) 504.12;    -   (hhhh)        1-(2-Methoxy-6-methyl-phenyl)-3-{3-[8-(pyridin-4-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₆H₂₃N₇O₂, MW═465.51 Mass Spec m/z (M⁺+1) 466.13;    -   (iiii)        1-(2-Methoxy-5-methyl-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF═C₂₇H₂₄N₆O₂, MW═464.52 Mass Spec m/z (M⁺+1) 465.13;    -   (jjjj)        1-{3-[8-(3-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-5-methyl-phenyl)-urea,        MF═C₂₇H₂₃ClN₆O₂, MW═498.96 Mass Spec m/z (M⁺+1) 499.19;    -   (kkkk)        1-{3-[8-(2-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-5-methyl-phenyl)-urea,        MF═C₂₇H₂₃ClN₆O₂, MW═498.96 Mass Spec mn/z (M⁺+1) 499.18;    -   (llll)        1-{3-[8-(Pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF═C₂₅H₁₈F₃N₇O, MW═489.45 Mass Spec m/z (M⁺+1) 490.31; and    -   (mmmm)        1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF═C₂₄H₁₇ClFN₇O, MW═473.89 Mass Spec m/z (M⁺+1) 474.28.

EXAMPLE 3

This example represents a generalized description the standard AKT-1Kinase Assay for testing compounds disclosed in this application.

In a final reaction volume of 40 microliters (μl), active recombinantN-terminus his-tagged AKT-1/PKB α kinase expressed in Sf21 cells (UBINo. 14–276; 50–100 ng; 19–38 nM; about 4.5–9 mU) was incubated in 25 mMTris pH 7.6; 5 mM beta-glycerophosphate; 2 mM DTT; 100 μM sodiumvanadate; 10 mM MgCl₂ in 96-well Pierce Reaci-Bind™ streptavidin-coatedhigh binding capacity coated white plate (Pierce #15502) coated withsaturating amounts of biotinylated Crosstide peptide (UBI #12–385;biotin-KGSGSGRPRTSSFAEG; 50 pmoles; about 1.25 μM) and initiated withthe addition of 2.5 μCi ³²P-γATP (specific activity 3000 Ci/mmole; 10mCi/ml; about 21 nM). Compounds were tested initially in duplicate wellsfor determination of initial IC₅₀ inhibition in half log serialdilutions starting at 100 μM with a final concentration of 2% DMSO.Following a 30 min incubation at 30° C., the reaction was stopped byaspiration and 4×100 μl washes with TBS plus 0.05% Tween-20 prior toaddition of 100 μl scintillant and counting in Beckman TopCountinstrument. Percent inhibition was calculated as [1-((AVECPM_(compound)−AVE CPM_(no peptide background))/(AVECPM_(no compound MAX)−AVE CPM_(no peptide background))))*100].Staurosporine, a general ATP competitive kinase inhibitor was used as areference compound and showed an IC₅₀ of approximately 60–100 nM forAKT-1 in the current assay format. Approximate S/N ratios are 8–12× withAVE CPM of Maximum about 15 k and no peptide background about 1.5 K.Improved S/N ratios can be obtained using higher amounts of either AKT-1kinase or ³²P-γATP. Cold ATP was not added in current format but hasbeen added at up to 200 μ/M in the presence of 5 μCi ³²P-γATP resultingin S/N ratios of approximately 5–10×.

EXAMPLE 4

A generalized description the standard assay to evaluate modulation ofcell growth in soft agar (using cell lines HCT-15 (colon cancer),MiaPaca2 (pancreatic cancer), MCF-7 (breast cancer) and a NIH3T3 clonestably over-expressing transfected myrAkt-1 human gene, for example) isas follows.

Preparation of the agar base layer: A quantity of 500 ml of 2×DMEM(phenol red free, Sigma Cat # D2902) is prepared, and sterile filtered.To that solution is added 10 ml of sodium pyruvate (Gibco, Cat #11360–070), 10 ml of penicillin/streptomycin (Gibco, Cat# 15140–122), 10ml of Glutamax (Gibco, cat# 33050–061) and 100 ml of heat-inactivatedFBS (Gemini) to make 2×DMEM complete media stock. Two stockconcentrations of Sea Plaque low melt agar (Biowhittaker, Cat # 431097),1%, and 0.6%, are prepared with ultra pure milliQ water, and sterilizedby autoclaving. To prepare the agar base layer for a 12–well plate(Falcon # 353042), 6 ml of the 2× DMEM stock is mixed with 6 ml of 1%agar stock, both at 37° C., and 1 ml of the resulting mixture is addedto each well of the 12 well plate, 3 hrs prior to setup of top layer.

Top layer with cells and compound for evaluation: Cells at 60–80%confluency (log growth) in T75 are trypsinized with 1 ml of 1× trypsinsolution (Gibco), neutralized with 10 ml of 1×DMEM 10% FBS and viablecells counted using a hemocytometer via trypan blue exclusion. A workingstock of 2.5×10⁴ cells/ml is prepared in 1×DMEM 10% FBS. A 15 mlcentrifuge tube is prepared for each concentration of compound tested induplicate wells of a 12 well plate. The following are added in order: 1ml of 2×DMEM stock at 37° C.; compound at 2× final desired concentration(using 4 microliter volume from a 1000× concentrated dilution series in100% DMSO); followed by 2,500 cells (using 100 microliters of 1×10⁴cell/ml working stock), and finally 1 ml of 0.6% agar stock at 37° C.Following careful mixing, 1 ml each is added to duplicate wells of the12-well plate. The plate is then placed in a 37° C., 5% CO₂, humidifiedincubator for 10 to 14 days and read. Rapid diffusion of CPD throughouttop and bottom agar layer results in final drug concentration of 1×.

Counting Colonies: After 10 days of incubation, the plates are removedfrom the incubator for photography and colony counting. Each well isscanned using an eyepiece with a micrometer guide and 5× phase optics.Colonies 50 micrometer or greater in diameter are scored as positive.Duplicate wells are averaged and percent inhibition calculated usingnumber of colonies in no compound control wells as 100%.

All compounds described in Example 1 were tested according to the aboveprotocol and determined to exhibit an IC₅₀ value less than or equal to25 micromolar.

All cited references are incorporated herein in their entirety. Whilepreferred embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations.

1. A compound having Formula 1:

a pharmaceutically acceptable salt, or mixture thereof, wherein R₁ ishydrogen; cyclo-(C₃–C₆ alkyl)-methyl; straight or branched chain C₁–C₇alkyl, in which the branched alkyl chains are allowed to also form a 3–7member heteroalkyl or alkyl ring; sulfonamide; C₁–C₆ alkoxy;(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy; (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl; mono-or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl); orphenyl which may be unsubstituted, mono-, di- or trisubstituted with oneor more of hydroxy, nitro, cyano, amino, sulfonamide, halogen, C₁–C₆alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,—S(C₁–C₆ alkyl ), mono- or di (C₁–C₆ alkyl)amino, mono-or di(C₁–C₆alkyl)amino(C₁–C₆ alkyl), or ester; R₂ is straight or branched chainC₁–C₇ alkyl, in which the branched alkyl chains are allowed to also forma 3–7 member heteroalkyl or alkyl ring; cyclo-(C₃–C₆ alkyl)-methyl;C₁–C₆ alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; phenyl or heteroaryl which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester;phenyoxy phenyl where each phenyl may be independently unsubstituted,mono-, di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester;phenyl or heteroaryl piperazine where the phenyl or heteroaryl ring maybe independently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono-or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester; and wherein R₂ can form a3–7 heteroalkyl or alkyl with R₁₀, R₁₁, or R₁₂; R₃ is hydrogen;carboxylic acid or ester; straight or branched chain C₁–C₆ alkyl, inwhich the branched alkyl chains are allowed to also form a 3–7 memberheteroalkyl or alkyl ring; phenyl or heteroaryl which may beunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or ester;phenyoxy phenyl where each phenyl may be independently unsubstituted,mono-, di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl) amino,amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester;phenyl or heteroaryl piperazine where the phenyl or heteroaryl ring maybe independently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono-or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl),—S(C₁–C₆ alkyl ), or carboxylic acid or ester; R₄ is hydrogen; straightor branched chain C₁–C₆ alkyl, in which the branched alkyl chains areallowed to also form a 3–7 member heteroalkyl or alkyl ring;(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; phenyl or heteroaryl which may beunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), -S(C₁–C₆ alkyl), or carboxylic acid or ester;phenyoxy phenyl where each phenyl may be independently unsubstituted,mono-,di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or ester; phenyl orheteroaryl piperazine where the phenyl or heteroaryl ring may beindependently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono-or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino (C₁–C₆ alkyl),—S(C₁–C₆ alkyl), or carboxylic acid or ester; or form a 3–7 memberheteroalkyl or alkyl with Z₁ or R₁; X is CH Z₁ is

wherein each occurrence of R₅ and R₆ is independently hydrogen straightor branched chain C₁–C₆ alkyl, sulfonamide, or halogen; m is 0, 1, or 2;and R₇ is hydrogen; straight or branched chain C₁–C₆ alkyl; phenyl whichmay be unsubstituted, mono-, di- or trisubstituted with one or more ofhydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl) , -S(C₁–C₆ alkyl), or carboxylic acid or ester; orheteroaryl which may be unsubstituted, mono-, di- or trisubstituted withone or more of hydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆alkyl)amino, amino(C₁–C₆ alkyl) , —S(C₁–C₆ alkyl ), or carboxylic acidor ester; and Z₂ is

wherein each occurrence of R₈ and R₉ is independently straight orbranched chain C₁–C₆ alkyl, sulfonamide, or halogen; n is 0, 1, or 2;and R₁₀–R₁₃ are each independently hydrogen; straight or branched chainC₁–C₆ alkyl; phenyl which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, (C₁–C₆perfluoroalkoxy, (C₁ –C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester; or heteroaryl which may beunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl) , —S(C₁–C₆ alkyl), or carboxylic acid or ester; andwherein, when R₃ is hydrogen and R₄ is hydrogen, or when R₃ and R₁ arehydrogen and Z₁ is

wherein m is 0, the combination of Z₂—R₂ is not hydrogen, hydroxy,halogen, hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,arylamide or alkoxy, or wherein when R₃ is hydrogen, R₄ and Z₁, or R₄and R₁ do not form a morpholino, piperazinyl, or 1,4diazepanyl groupwhen the combination of Z₂—R₂ is hydrogen, hydroxy, halogen,hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,arylamide or alkoxy.
 2. A compound having Formula 2:

a pharmaceutically acceptable salt or mixtures thereof, wherein R₁ isphenyl which may be unsubstituted, mono-, di- or trisubstituted with oneor more of hydroxy, nitro, cyano, amino, sulfonamide, halogen, C₁–C₆alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,—S(C₁–C₆ alkyl ), mono- or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆alkyl)amino(C₁–C₆ alkyl), or ester; R₂ is phenyl or heteroaryl which maybe unsubstituted, mono-, di- or trisubstituted with one or more ofhydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), -S(C₁–C₆ alkyl ), or carboxylic acid or ester;phenyoxy phenyl where each phenyl may be independently unsubstituted,mono-,di - or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfiucroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkoxy,(C₁–C₆)-alkyi-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester; phenyl orheteroaryl piperazine where the phenyl or heteroaryl ring may beindependently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono-or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl),—S(C₁–C₆ alkyl), or carboxylic acid or ester; and wherein R₂ can form a3–7 heteroalkyl or alkyl with R₁₀, R₁₁, or R₁₂; R₃ is hydrogen; orcarboxylic acid or ester; R₄ is hydrogen; straight or branched chainC₁–C₆ alkyl, in which the branched alkyl chains are allowed to also forma 3–7 member heteroalkyl or alkyl ring; or (C₁–C₆)-alkyl-oxy-C₁–C₆)alkyl; Xis CH Z₁ is

wherein each occurrence of R₅ and R₆ is independently hydrogen straightor branched chain C₁–C₆ alkyl, sulfonamide, or halogen; m is 0, 1, or 2;and Z₂ is

wherein R₁₀—R₁₃ are each independently hydrogen; straight or branchedchain C₁–C₆ alkyl; phenyl which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,haiogen, C₁–C₆ alkyl, C₁–C₆ aikoxy, C₁–C₆ perfluoroalkyl, C₁–C₆perfluoroalkoxy, (C₁ –C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁ –C₆)-alkyl-oxy-C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆alkyl), —S (C₁–C₆ alkyl ), or carboxylic acid or ester; or heteroarylwhich may be unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C ₆)alkyl, mono- ordi(C₁–C₆ alkyl)amino, amino(C₁–C₆ alkyl) , —S(C₁–C₆ alkyl), orcarboxylic acid or ester; and wherein, when R₃ is hydrogen and R₄ ishydrogen, or when R₃ and R₁ are hydrogen and Z₁ is

wherein m is 0, the combination of Z₂–R₂ is not hydrogen, hydroxy,halogen, hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,arylamide or alkoxy, or wherein when R₃ is hydrogen, R₄ and Z₁, or R₁and R₁ do not form a morpholino, piperazinyl, or 1 ,4-diazepanyl groupwhen the combination of Z₂—R₂ is hydrogen, hydroxy, halogen,hydroxyamide, amino, hydroxyalkyl, aminoalkylamide, alkylamide,arylamide or alkoxy.
 3. A compound having Formula 3:

a pharmaceutically acceptable salt, or mixtures thereof, wherein R₁ ishydrogen; cyclo-(C₃–C₆ alkyl)-methyl; stralght or branched chain C₁–C₇alkyl, in which the branched alkyl chains are allowed to also form a 3–7member heteroalkyl or alkyl ring; sulfonamide; (C₁–C₆ alkoxy;(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆); mono- ordi(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl); orphenyl which may be unsubstituted, mono-, di- or trisubstituted with oneor more of hydroxy, nitro, cyano, amino, sulfonamide, halogen, C₁–C₆alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,—S(C₁–C₆ alkyl ), mono- or di(C₁–C₆ alkyl) amino, mono-or di(C₁–C₆alkyl)amino(C₁–C₆ alkyl), or ester; R₂ is straight or branched chainC₁–C₇ alkyl, in which the branched alkyl chains are allowed to also forma 3–7 member heteroalkyl or alkyl ring; cyclo-(C₃–C₆ alkyl)-methyl;C₁–C₆ alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy; (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl; phenyl or heteroar which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or ester;phenyoxy phenyl where each phenyl may be independently unsubstituted,mono-, di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, (₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆ alkyl), -S(C₁–C₆ alkyl ), or carboxylic acid or ester;phenyl or heteroaryl piperazine where the phenyl or heteroaryl ring maybe independently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, ammo, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkyl, mono-or di(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl), —S(C₁–C₆ alkyl ), or carboxylic acid or ester; and wherein R₂ can form a3–7 heteroalkyl or alkyl with R₁₂; R₃ is hydrogen; carboxylic acid orester; straight or branched chain C₁–C₆ alkyl, in which the branchedalkyl chains are allowed to also form a 3–7 member heteroalkyl or alkylring; phenyl or heteroaryl which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amiino, amino(C₁–C₆ alkyl),—S(C₁–C₆ alkyl ), or carboxylic acid or ester; phenyoxy phenyl whereeach phenyl may be independently unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆ alkyl)amino, amino(C₁–C₆alkyl), —S(C₁–C₆ alkyl), or carboxylic acid or ester; phenyl orheteroaryl piperazine where the phenyl or heteroaryl may beindependently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆ perfluoroalkoxy,(C₁–C₆)-oxy-(C₁–C₆)-alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- ordi(C₁–C₆ alkyl)amino, mono- or di(C₁–C₆ alkyl)amino(C₁–C₆ alkyl),—S(C₁–C₆ alkyl), or carboxylic acid or ester; R₄ is hydrogen; straightor branched chain C₁–C₆ alkyl, in which the branched alkyl chahins areallowed to also form a 3–7 member heteroalkyl or alkyl ring;(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl; phenyl or heteroaryl which may beunsubstituted, mono-, di- or trisubstituted with one or more fo hydroxy,nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C_(6)-alkyl-oxy-(C) ₁–C₆) alkyl, mono-or di(C₁–C₆)amino,amino(C₁–C₆), —S(C₁–C₆ alkyl), or carboxylic acid or ester; phenyoxyphenyl where each phenylmay be independently unsubstituted, mono-,di -or trisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, sulfonamide. C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl,C₁–C₆ perfluoroalkoxy, (C₁–C₆) -alkyl-oxy-(C₁–C₆) alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆)amino, amino (C₁–C₆),—S(C₁–C₆), or carboxylic acid or ester; phenyl or heteroaryl piperazinewhere the phenyl or heteroaryl ring may be independently unsubstituted,mono-,di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, sulfonamide, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁C₆ perfluoroalfoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆) alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆)amino, mono- ordi(C₁–C₆)amino(ac₁–C₆), —S (C₁–C₆ alkyl), or carboxylic acid or ester;or form a 3–7 member heteroalkyl or alkyl with Z₁ or R₁; X is CH Z₁ is

wherein each occurrence of R₅ and R₆ is independently hydrogen straightor branched chain C₁–C₆ alkyl, sulfonamide, or halogen; m is 0, 1, or 2;and R₇ hydrohen; straight or branched chain C₁–C₆ alkyl; phenyl whichmay be unsubstituted, mono-, di- or trisubstituted with one or more ofhydroxy, nitrom, cyano, amono, halogen, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆)amino, amino(C₁–C₆) ,—S(C₁–C₆ alkyl), or carbocylic acid or ester; or heteroaryl which may beunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆perfluoroalkyl, C₁–C₆ perfluoroalkoxy, (C₁–C₆) -alkyl-oxy-(C₁–C₆)alkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkyl, mono- or di(C₁–C₆alkyl)amino, amino(C₁–C₆) , —S(C₁–C₆), or carboxylic acid or ester; andwherein R₁₂ and R₁₃ are each independently hydrogen; straight orbtanched chain C₁–C₆ alkyl; phenyl which may be unsubstituted, mono-,di- or trisubstituted with one or more of hydroxy, niteo, cyano, amino,halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, (C₁–C₆)-alkyl-oxy -(C₁–C₆)alkoxy,mono- or di(C₁–C₆ alkyl)amino, amino(C₁–c₆ alkyl), —S(C₁–C₆), orcarboxylic acid or ester; or heteroaryl which may be unsubstituted,mono-, di- or trisubstituted with one or more of hydroxy, nitro, cyano,amino, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ perfluoroalkyl, C₁–C₆perfluoroalkoxy, (C₁–C₆)-alkyl-oxy-(C₁–C₆)alkoxy,(C₁–C₆)-alkyl-oxy-(C₁–C₆) alkyl, mono- or di(C₁–C₆ alkyl)amino,amino(C₁–C₆) , —S(C₁–C₆), or carboxylic acid or ester.
 4. A compound asin claim 1 or a pharmaceutically acceptable saly thereof, wherein thecompound is1-(4-{8-[(3-Chloro-benyl)-methyl-amino]-imidao[1,2-a]pyrain-6yl}-phenyl)-3-(2-chloro-phenyl)-urea.5. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-chloro-phenyl)-urea.
 6. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(2-methoxy-phenyl)-urea.
 7. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-chloro-phenyl)-urea.
 8. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-chloro-phenyl)-urea.
 9. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-trifluoromethyl-phenyl)-urea.
 10. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-trifluoromethoxy-phenyl)-urea.
 11. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(2-methylsulfanyl-phenyl)-urea.
 12. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[Methyl-(4-methyl-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(2-methylsulfanyl-phenyl)-urea.
 13. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(4-Chloro-phenyl)-3-(3-{8-[methyl-(4-methyl-benzyl)-amino]-iniidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea.14. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is1-(3-{8-[Methyl-(4-methyl-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-o-tolyl-urea.
 15. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is1-(4-Chloro-phenyl)-3-{3-[8-(3 ,4-dihydro- 1H-isoquinolin-2-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea.
 16. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is 1-{3-[8-(3 ,4-Dihydro- 1H-isoquinolin-2-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methylsulfanyl-phenyl)-urea.
 17. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is 1-{3-[8-(3 ,4-Dihydro-1H-isoquinolin-2-yl)-imidazo[1 ,2-a]pyrazin-6-yl]-pheny}-3-o-tolyl-urea.18. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is 1-{3-[8-(3 ,4-Dihydro- 1H-isoquinolin-2-yl)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-phenyl)-urea.
 19. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is8-[(4-Chloro-benzyl)-methyl-amino]-6-{3-[3-(2-trifluoromethyl-phenyl)-ureido]-phenyl}-imidazo [1 ,2-a]pyrazine-3-carboxylic acid ethyl ester.
 20. A compoundas in claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is8-[(4-Chloro-benzyl)-methyl-amino]-6-[3-(3-o-tolyl-ureido)-phenyl]-imidazo[1,2-a]pyrazine-3-carboxylicacid ethyl ester.
 21. A compound as in claim 1 or a pharmaceuticallyacceptable salt thereof, wherein the compound is8-[(4-Chloro-benzyl)-methyl-amino]-6-{3-[3-(4-chloro-phenyl)-ureido]-phenyl}-imidazo[1 ,2-a]pyrazine-3-carboxylic acid ethyl ester.
 22. A compoundas in claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[methyl-(4-methyl-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea.
 23. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo [1,2-a]pyrazin-6-yl}-phenyl) -3-(3-chloro-4-fluoro-phenyl)-urea.
 24. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-benzyl) -3-(4-chloro-phenyl)-urea.
 25. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-benzyl) -3-(3-chloro-4-fluoro-phenyl)-urea.
 26. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-ethyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-tolyl-urea.
 27. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-ethyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-chloro-phenyl)-urea.
 28. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8-[(4-Chloro-benzyl)-ethyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-chloro-4-fluoro-phenyl)-urea.
 29. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-o-tolyl-urea.
 30. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-chloro-4-fluoro-phenyl)-urea.
 31. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-tolyl-urea.
 32. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-chloro-phenyl)-urea.
 33. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8-[(4-Chloro-benzyl)-propyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-trifluoromethyl-phenyl)-urea.
 34. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-chloro-phenyl)-urea.
 35. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8-[Butyl-(4-chloro-benzyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-trifluoromethyl-phenyl)-urea.
 36. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[Butyl-(4-chloro-benzyl)-aminol]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-chloro-4-fluoro-phenyl)-urea.
 37. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3-trifluoromethyl-phenyl)-urea.
 38. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-o-tolyl-urea.
 39. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is1-{3-[8-(Benzyl-methyl-amino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl) -urea.
 40. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-trifluoromethoxy-phenyl)-urea.
 41. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(5-fluoro-2-trifluoromethyl-phenyl)-urea.42. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3 ,5-dichloro-phenyl)-urea.
 43. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(3,4-dichloro-phenyl)-urea.
 44. A compoundas in claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8-[(2-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -3-(4-chloro-phenyl)-urea.
 45. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is1-(4-Chloro-benzyl)-3-(3-{8-[(4-chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea.46. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyi)-3-(4-chloro-phenyl)-urea.
 47. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 1-(3-{8[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea.
 48. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-chloro-3-fluoro-phenyl)-urea.
 49. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-(2-methoxy-ethyl)-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-urea.50. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is(2-Methoxy-benzyl)-{6-[3-(4-methoxy-benzylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl}-amine.
 51. A compound as in claim 1 or a pharmaceutically acceptablesalt thereof, wherein the compound is1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-phenyl-urea.
 52. A compound as in claim 1or a pharmaceutically acceptable salt thereof, wherein the compound is1-(2-Chloro-phenyl)-3-{4[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl }-urea.
 53. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-phenyl)-urea.
 54. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-methoxy-phenyl)-urea.
 55. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is N-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -benzenesulfonamide.
 56. A compound as inclaim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is N-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -benzamide.
 57. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is4-Chloro-N-(3-{8-[(4-chloro-benzyl)-methyl-amino]-imidazo[1 ,2-a]pyrazin-6-yl}-phenyl)-benzamide.
 58. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is2-Chloro-N-(3-{8-[(4-chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide.
 59. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is(4-{8-[(3-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -piperidin- 1 -yl-methanone.
 60. A compoundas in claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is (4-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl) -piperidin- 1 -yl-methanone.
 61. A compoundas in claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 4-{6-[4-(Piperidine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino }-benzoic acid ethyl ester.
 62. A compound as inclaim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 4-(6-{3-[3-(4-Chloro-phenyl)-ureido]-phenyl}1 -imidazo[1,2-a]pyrazin-8-ylamino) -benzoic acid ethyl ester.
 63. A compound as inclaim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 4-(6-{3-[3-(2-Methylsulfanyl-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid ethyl ester.
 64. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-{8-[(4-Chloro-benzyl)-methyl-amino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(2-methylsulfanyl-phenyl)-urea.
 65. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is {4-[8-(4-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-piperidin-1-yl -methanone.
 66. A compound asin claim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound is 3-Methoxy-N- {3-[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide.
 67. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is2-Methoxy-N- {3-[8-(2-methoxy-benzylamino)-irnidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide.
 68. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-(3-Chloro-4-fluoro-phenyl)-3[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl) -phenyl]-urea.
 69. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-(4-Chloro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea.
 70. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-[3-(8-Phenylamino-iniidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-(3-trifluoromethyl -phenyl)-urea.
 71. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(2-Chloro-5-trifluoromethyl-phenyl)-3[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea.72. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is1-(4-Chloro-phenyl)-3-{3-[8-(4-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6]-phenyl}-urea.
 73. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-{3-[8-(4-Chloro-phenylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea.
 74. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-(3-Chloro-4-fluoro-phenyl)-3-{3[8-(3-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea.75. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is1-(4-Chloro-phenyl)-3-{3[8-(3-chloro-phenylamino)-imidazo[1 ,2-a]pyrazin-6-yl]-phenyl}-urea.
 76. A compound as in claim 1 or a pharmaceuticallyacceptable salt thereof, wherein the compound is1-{3-[8-(3-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea.
 77. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea.78. A compound as in claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is 1-[3-(8-Phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-(4-trifluoromethyl -phenyl) -urea.
 79. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is1-(2-Methoxy-5-methyl-phenyl)-3-[3-(8-phenylamino-iniidazo[1,2-a]pyrazin-6-yl) -phenyl]-urea.
 80. A compound as in claim 1 or apharmaceutically acceptable salt thereof, wherein the compound is1-{3-[8-(3-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-5-methyl-phenyl)-urea.
 81. Acompound as in claim 1 or a pharmaceutically acceptable salt thereof,wherein the compound is 1-{3-[8-(2-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-5-methyl-phenyl)-urea.
 82. Apharmaceutical composition comprising a compound or salt according toclaims 1 to 44, 45 to 78, or 79 to 81, combined with at least onepharmaceutically acceptable carrier or excipient.